Megalin受体介导的Aleglitaza-LMCS-PEG-SkQR1聚合物胶束对肾缺血再灌注损伤的靶向修复作用研究

肾缺血再灌注损伤（IRI）迄今尚无安全有效的药物干预手段。肾小管上皮细胞是肾脏发生IRI时的主要受损细胞，而线粒体损伤是其发生的重要机制。SkQR1是当前较具研究前景的线粒体靶向抗氧化剂，但治疗IRI仍受限于药物靶向性较弱等问题。根据低分子壳聚糖（LMCS）修饰的纳米载体能被肾小管上皮细胞的megalin受体特异性内吞的特性，课题组前期构建的LMCS-PEG-SkQR1载药胶束初步证实对肾脏具有靶向作用，药效学试验证实该载药胶束能持续改善IRI大鼠肌酐和尿素氮水平。在此基础上，课题组将采用能提高megalin受体表达的Aleglitazar对载药胶束进行修饰，并进一步考察共聚物纳米载体的理化性质，从细胞和动物水平评价纳米载体对肾IRI的抗氧化作用。本课题旨在为建立高效、安全的线粒体靶向治疗IRI新方案提供科学依据。

So far, there is still no safe and effective drug intervention method for renal ischemia-reperfusion injury (IRI). Renal tubular epithelial cells are the main damaged cells of the renal IRI, while mitochondrial damage is a significant mechanism for its occurrence. SkQR1 is a promising antioxidant for mitochondria targeting, but the treatment of IRI is still limited by weak drug targeting. It is reported that the low molecular weight chitosan (LMCS) modified conjugates can realize renal targeting therapy by megalin receptor-mediated endocytosis. On this basis, the SkQR1-loaded PEG-LMCS micelles, which can be successfully transported to renal tissue were preliminary evidenced in our previous study. Pharmacodynamics experiment indicated that the micelles can improve creatinine and urea nitrogen level of IRI rat. Besides, on this basis, the research group will modify the drug loaded micelles with Aleglitazar which can enhance the expression of megalin receptor, and further investigate the physicochemical properties of the drug loaded micelles. Finally, the antioxidant effect of nano carriers on renal IRI from cell and animal level will be evaluated. In all, the aim of this study is to provide a scientific basis for the establishment of a highly efficient and safe mitochondrial targeted therapy method for IRI.